rs1057516055

Variant names:

• chrM-1661-A-G
• rs1057516055
• unassigned_transcript_4786:c.60A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: TRNV stop_lost
• Scores: Mitotip Uncertain 9.1
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:4 Charcot-Marie-Tooth-(CMT)
• Conservation: PhyloP100: 0.0530

Genes affected

TRNV (HGNC:7500): (mitochondrially encoded tRNA valine)

RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNV	unassigned_transcript_4786	c.60A>G	p.Ter20Trpext*?	stop_lost	Exon 1 of 1
RNR2	unassigned_transcript_4787	n.-10A>G		upstream_gene_variant
RNR1	unassigned_transcript_4785	n.*60A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.0 AC: 1

Gnomad homoplasmic AF: 0.000035 AC: 2 AN: 56398

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56398

Mitomap

Charcot-Marie-Tooth-(CMT)

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1 Pathogenic:1 Uncertain:1

Aug 30, 2023

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

It is observed in the gnomAD v3.1.2 (https://gnomad.broadinstitute.org) dataset at heteroplasmic allele frequency of 0.005% and homoplasmy allele frequency of 0.003%. Predicted Consequence/Location: Mitochondrial variant The variant has been reported to be associated with MT-TV related disorder (ClinVar ID: VCV000370043 /Mitomap PMID: 32715519, 28027978). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Jan 22, 2025

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Spastic paraplegia, mitochondrial Pathogenic:1

Jan 22, 2025

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Uncertain:1

Oct 23, 2023

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.1661A>G variant in MT-TV has been reported in two unrelated families (PS4_supporting). Limited phenotypic details are provided in the first reported family (Patient 6 in Bacalhau et al., 2017, PMID: 28027978) however a subsequent publication reported the proband in this family had seizures, hypotonia, developmental delay, elevated blood lactate, and combined deficiency of electron transport chain enzyme activities (PMID: 32715519). The heteroplasmy level and information on family members and/or testing in family members were not reported in this first kindred. The second family reported was a large kindred from the Venezuelan Andes with axonal Charcot-Marie-Tooth (CMT) disease (motor and sensory neuropathy). Muscle weakness, muscle atrophy, and ataxia were also seen in the affected individuals in this family (Fay et al., 2020, PMID: 32715519). Muscle biopsies performed in several individuals showed denervation and reinnervation, in addition to mitochondrial hyperplasia, mildly increased glycogen, and the presence of mitochondrial crystalline arrays. Combined respiratory chain enzyme deficiencies were also seen in affected individuals from this kindred. The variant was present at homoplasmy in blood and/or muscle in both affected and unaffected individuals from this kindred. There are no reported de novo occurrences on this variant to our knowledge. The computational predictor MitoTIP suggests this variant is benign (27.6 percentile; BP4).This variant is present in population databases (MITOMAP: 1/61,168 sequences, AF=0.002%, haplogroup (Hg) H1c; Helix: 2/195,983 (0.001%), also 19 heteroplasmic occurrences, homoplasmic occurrences in Hg I and V, heteroplasmic in multiple haplogroups; and gnomAD v3.1.2: 2/56,398 (0.004%), also three heteroplasmic occurrences (heteroplasmy levels: 10-20%; 20-30%; 90-100%), one in Hg T, one in H, one in B, one in K, one in L3). Given the frequency of this variant, it does not meet PM2 criterion. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, BP4 -

Epilepsy;C0424605:Developmental delay;C1853743:Axial hypotonia;CN239816:Hyperlactaemia Uncertain:1

Nov 21, 2016

Center for Neuroscience and Cell Biology, University of Coimbra, Portugal

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	9.1
Hmtvar	Benign	0.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057516055; hg19: chrM-1663;